NADPH Oxidase-Derived Reactive Oxygen Species Mediate Decidualization of Human Endometrial Stromal Cells in Response to Cyclic AMP Signaling
NADPH Oxidase-Derived Reactive Oxygen Species Mediate Decidualization of Human Endometrial Stromal Cells in Response to Cyclic AMP Signaling
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DOI：
10.1210/en.2010-0899
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发表时间：
2011-02-01
期刊：
影响因子：
4.8
通讯作者：
Brosens, Jan J.
中科院分区：
文献类型：
--
作者：
Al-Sabbagh, Marwa;Fusi, Luca;Brosens, Jan J.
人子宫内膜间质细胞分化为特化的蜕膜细胞是胚胎着床和胚胎存活的关键。这种分化过程的启动严格依赖于cAMP水平的升高，但控制个体标记基因（如催乳素（PRL）和IGFBP1）表达的信号中间体仍然缺乏特征。在本研究中，我们发现在烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶抑制剂（二苯碘）或活化剂（罗布麻碱）处理原代培养物后，camp依赖性的去个性化可以减弱或增强。时间过程分析表明，cAMP增强了内源性活性氧的产生，在刺激12小时后明显增加，这与个体PRL和IGFBP1表达的急剧增加相吻合。Rho GTPase RAC1的敲除会使NADPH氧化酶同源物NADPH氧化酶(NOX)-1、NOX-2和NOX-3的激活失活，但对PRL或IGFBP1的表达没有影响。相反，NOX-4或其辅助因子p22（PHOX）的沉默抑制了这两种标志物的表达。最后，我们发现NOX-4/p22（PHOX）复合物调节CCAAT/增强子结合蛋白- β的dna结合活性，CCAAT/增强子结合蛋白- β是人子宫内膜基质细胞分化的关键调节因子。因此，NOX-4激活和活性氧信号在启动子宫内膜蜕膜反应中起着不可或缺的作用。（内分泌学152:730-740,2011）
Differentiation of human endometrial stromal cells into specialized decidual cells is critical for embryo implantation and survival of the conceptus. Initiation of this differentiation process is strictly dependent on elevated cAMP levels, but the signal intermediates that control the expression of decidual marker genes, such as prolactin (PRL) and IGFBP1, remain poorly characterized. Here we show that cAMP-dependent decidualization can be attenuated or enhanced upon treatment of primary cultures with a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor (diphenylen iodonium) or activator (apocynin), respectively. Time-course analysis demonstrated that cAMP enhances endogenous reactive oxygen species production, apparent after 12h of stimulation, which coincides with a dramatic increase in decidual PRL and IGFBP1 expression. Knockdown of the Rho GTPase RAC1, which disables activation of the NADPH oxidase homologs NADPH oxidase (NOX)-1, NOX-2, and NOX-3, had no effect on PRL or IGFBP1 expression. In contrast, silencing of NOX-4, or its cofactor p22(PHOX), inhibited the expression of both decidual markers. Finally, we show that the NOX-4/p22(PHOX) complex regulates the DNA-binding activity of CCAAT/enhancer binding protein-beta, a key regulator of human endometrial stromal cell differentiation. Thus, NOX-4 activation and reactive oxygen species signaling play an integral role in initiating the endometrial decidual response in preparation of pregnancy. (Endocrinology 152: 730-740, 2011)